Jean-Pierre Vilardaga, Lisa J Clark, Alex D White, Ieva Sutkeviciute, Ji Young Lee, Ivet Bahar
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The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":"44 3","pages":"474-491"},"PeriodicalIF":22.0000,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461325/pdf/","citationCount":"0","resultStr":"{\"title\":\"Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.\",\"authors\":\"Jean-Pierre Vilardaga, Lisa J Clark, Alex D White, Ieva Sutkeviciute, Ji Young Lee, Ivet Bahar\",\"doi\":\"10.1210/endrev/bnac032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. 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引用次数: 0
摘要
G 蛋白偶联受体(GPCR)通过 G 蛋白发出信号的经典范式是基于下游反应相对短暂且局限于细胞表面的观点,但近年来,随着几种受体的鉴定,这种观点得到了修正,这些受体在配体-受体复合物内化后会从亚细胞区进行持续的信号反应。这种现象最初是在甲状旁腺激素(PTH)1 型受体(PTH1R)上发现的,PTH1R 是维持体内正常钙和磷酸盐水平的重要 GPCR,具有与 PTH 结合后生成或分解骨骼的自相矛盾的能力。该受体调节的各种生物过程被认为取决于其介导环磷酸腺苷(cAMP)信号传导的各种模式的能力。其中包括质膜上的瞬时信号传导和由 PTH 介导的早期内体中内化的 PTH1R 的持续信号传导。在此,我们讨论了最近的结构、细胞信号和体内研究,这些研究揭示了 PTH1R 通过 cAMP 信号转导的空间与时间维度的潜在药理作用。值得注意的是,分子动力学模拟与基于弹性网络模型的方法相结合,揭示了如何通过受体内部以及肽类激素结合位点与 G 蛋白耦合界面之间的结构编码异生耦合来实现对 PTH 信号反应的精确调节。目前正在探索最新发现的意义,以解决以下关键问题:受体信号传导中的位置偏差如何对药理功能产生影响,以及如何对像 PTH1R 这样的困难靶点进行药物治疗,从而发现治疗代谢性骨病和矿物质疾病的非肽类小分子候选药物。
Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.
The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.
期刊介绍:
Endocrine Reviews, published bimonthly, features concise timely reviews updating key mechanistic and clinical concepts, alongside comprehensive, authoritative articles covering both experimental and clinical endocrinology themes. The journal considers topics informing clinical practice based on emerging and established evidence from clinical research. It also reviews advances in endocrine science stemming from studies in cell biology, immunology, pharmacology, genetics, molecular biology, neuroscience, reproductive medicine, and pediatric endocrinology.